Prodrugs of 6-mercaptopurine and 6-mercaptopurine ribosides and therapeutic compositions and methods employing them

ABSTRACT

Novel, transient prodrug forms of biologically active agents containing mercapto groups have (i) the structural formula (I): ##STR1## wherein X is O, S, or NR 5  ; 
     R 1  S is the residue of any biologically active agent R 1  SH; 
     R 2  is selected from the group consisting of straight or branched chain alkyl having from 1 to 20 carbon atoms; aryl having from 6 to 10 carbon atoms; cycloalkyl having from 3 to 8 carbon atoms; alkenyl having from 2 to 20 carbon atoms; cycloalkenyl having from 4 to 8 carbon atoms; alkynyl having from 2 to 20 carbon atoms; aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl, alkynylaryl, loweralkanoyloxyalkyl, carboxyalkyl, and lower alkanoyloxyalkyl wherein alkyl, aryl, alkenyl and alkynyl are as defined above; saturated or unsaturated monoheterocyclic or polyheterocyclic, or fused heterocyclic, either directly bonded to the carbonyl function or linked thereto via an alkylene bridge, containing from 1 to 3 of any one or more of the heteroatoms N, S or O in each heterocyclic ring thereof and each such ring being from 3- to 8- membered; and mono- or polysubstituted derivatives of the above, each of said substituents being selected from the group consisting of lower akyl, lower alkoxy, lower acyl, lower acyloxy, halo, haloloweralkyl, cyano, carbethoxy, loweralkylthio, amino, nitro, loweralkylamino, diloweralkylamino, carboxyl, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl and ##STR2## wherein R 4  is hydrogen or alkyl having from 1 to 10 carbons; 
     R 3  is hydrogen, R 2 , lower acyl, cyano, haloloweralkyl, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl, --CH 2  ONO 2  and --CH 2  OCOR 2  ; 
     R 5  is hydrogen or lower alkyl; and further wherein 
     R 2  and R 3  may be taken together to form a cyclizing moiety selected from the group consisting of ##STR3## with the proviso that when R 1  S is the residue of a sulfur containing amino acid, then X cannot be NR 5  ; 
     (ii) the structural formula (I) wherein ##STR4##  is the residue of any naturally occurring protein amino acid, the residue of any N-substituted naturally occurring amino acid, which N-substituent is lower alkyl or any amino acid protective group cleavable via hydrogenolysis or hydrolysis, or the residue of an N,N-lower dialkyl of C 4  -C 7  cycloalkylamino acid; and 
     (iii) the non-toxic, pharmaceutically acceptable salts thereof.

RELATED APPLICATION

This application is a continuation-in-part of co-pending applicationSer. No. 290,625 filed Aug. 3, 1981 which in turn is a continuation ofapplication Ser. No. 141,981 filed Apr. 21, 1980, both now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel, transient prodrug derivatives ofthe biologically active compounds which contain a mercapto moiety, and,more especially, relates to certain acyl-X-methylthioether latentiatedforms of such thio compounds.

As employed in this application, the expression "prodrug" denotes aderivative of a known and proven prior art compound, which derivative,when absorbed into the bloodstream of a warm-blooded animal, "cleaves"in such a manner as to release the proven drug form and permits the sameto attain a higher bioavailability level than that which could beobtained if the proven drug form, per se, was administered.

Furthermore, also as used in this application, the term "transient"denotes "cleavage" of the compounds of this invention in such a mannerthat the proven drug form is released and the remaining "cleaved" moietyis non-toxic and metabolized in such a manner that non-toxic, metabolicproducts are produced.

2. Description of the Prior Art

It is well known to this art that the biologically active compoundswhich contain a mercapto group (--SH) and their salts, e.g., cysteine,cysteine methyl ester, N-acetylcysteine, penicillamine, dimercaprol,thiopental, 2-mercaptopyridine N-oxide, methimazole, propylthiouracil,N-(2-methyl-3-thio-propionyl)proline, 2-thiouracil, 6-mercaptopurine,glutathione, 6-thioguanine, 6-thioguanosine, 6-mercaptopurineriboside,as well as corresponding protected ester derivatives and salts areuseful active agents for the treatment or management of a wide varietyof disease states or conditions, e.g., cancer, psoriasis, hypertension,fungal infections, hyperthyroidism, metal poisoning, excess mucus, pain(general anesthesia).

Nevertheless, it too is well known to the art that such mercaptocontaining compounds, and the various art-recognized therapeuticallyactive derivatives thereof, are characterized by certain inherentdisadvantages, notably serious bioavailability and physiologicalavailability problems upon administration. Such reduced availability canbe attributed in part to poor lipid solubility [by reason of thepresence of the hydrophilic mercapto group], and also to metaboliclosses during and following conventional administration. Otherdisadvantages associated with the prior art compounds are instability toboth air and light, and same are subject to chemical attack by manyagents that are conventionally used in pharmaceutical preparations, aswell as a variety of other unfavorable pharmacodynamic properties.

Thus, there exists a clear and present need for novel latentiated formsof biologically active substances containing mercapto moieties whichderivatives would be devoid of those disadvantages and drawbacks that todate have characterized the prior art compounds.

SUMMARY OF THE INVENTION

Accordingly, a major object of the present invention is the provision ofa novel class of prodrugs of biologically active compounds which containmercapto groups.

Another object of this invention is the provision of a novel class ofmercapto compound prodrugs that is essentially free from the unwantedeffects associated with the prior art.

Still another object of the invention is to provide a new and usefulclass of latentiated mercapto compounds which is characterized byenhanced stability and solubility, can be administered in standardpharmaceutical formulations to warm-blooded animals to elicit a local,topical or systemic physiological or pharmacological beneficial effect,and which exhibits enhanced bioavailability and physiologicalavailability.

Yet another object is to provide a novel class of prodrugs ofbiologically active compounds which contain mercapto groups which willelicit a more effective therapeutic response, at lower concentrations ordosage levels, than its parent molecules.

Other objects, features and advantages of the invention will be apparentto those skilled in the art from the detailed description of theinvention which follows.

DETAILED DESCRIPTION OF THE INVENTION

More particularly according to this invention, all of the aforenotedobjects, features and advantages thereof are provided by the novelprodrugs of biologically active mercaptan containing compounds

(i) having the structural formula (I): ##STR5## wherein X is O, S or NR⁵;

R¹ is the deprotonated residue of a biologically active agent R¹ SH suchas

(a) thiopurine, especially 6-mercaptopurine or 6-mercaptopurineriboside;

(b) 6-thioguanosine;

(c) thiopental;

(d) N-(2-methyl-3-thiopropionyl)proline or an ester or amide thereof;

(e) N-acetyl cysteine;

(f) cysteine methyl ester;

(g) dimercaprol;

(h) penicillamine;

(i) glutathione;

(j) 2-thiopyridine-N-oxide;

(k) 2-thiouracil;

(l) 6-thioguanine; or

(m) methimazole;

R² is

(a) straight or branched chain alkyl having from 1 to 20 carbon atomsespecially methyl, ethyl, isopropyl, t-butyl, pentyl or hexyl;

(b) aryl having from 6 to 10 carbon atoms especially phenyl, substitutedpenyl or naphthalene;

(c) cycloalkyl having from 3 to 8 carbon atoms especially cyclopentyl,or cyclohexyl;

(d) alkenyl having from 2-20 carbon atoms especially C₂₋₆ alkenyl suchas vinyl, allyl, or butenyl;

(e) cycloalkenyl having from 5 to 8 carbon atoms especiallycyclopentenyl or cyclohexenyl;

(f) alkynyl having from 2 to 20 carbon atoms especially C₂₋₆ alkynyl forexample, ethynyl, propynyl or hexynyl;

(g) aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl or alkynylarylwherein alkyl, aryl, alkenyl and alkynyl are as previously defined;

(h) loweralkoxycarbonyl especially C₁₋₆ alkoxycarbonyl such asmethoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl andcyclopentoxycarbonyl;

(i) carboxyalkyl or alkanoyloxyalkyl especially carboxy-C₁₋₆ alkyl suchas formyloxymethyl and formyloxypropyl; or C₁₋₆ (alkylcarboxyalkyl) suchas acetoxymethyl, n-propanoyloxyethyl and pentanoyloxybutyl;

(j) saturated or unsaturated monoheterocyclic or polyheterocyclic, orfused heterocyclic, either directly bonded to the carbonyl function orlinked thereto via an alkylene bridge, containing from 1 to 3 of any oneor more of the heteroatoms N, S or O in each heterocyclic ring thereofand each such ring being from 3- to 8-membered; and

(k) mono- or polysubstituted derivatives of the above, each of saidsubstituents being selected from the group consisting of lower alkyl;lower alkoxy; lower alkanoyl; lower alkanoyloxy; halo especially bromo,chloro, or fluoro; haloloweralkyl especially fluoro, chloro orbromoloweralkyl such as trifluoromethyl and 1-chloropropyl; cyano;carbethoxy; loweralkylthio, especially C₁₋₆ loweralkylthio such asmethylthio, ethylthio and n-propylthio; nitro; carboxyl; amino;loweralkylamino especially C₁₋₆ alkylamino, for example, methylamino,ethylamino and n-butylamino; diloweralkylamino especially di(C₁₋₆loweralkyl)amino such as N,N-dimethylamino, N,N-diethylamino andN,N-dihexylamino; carbamyl; loweralkylcarbamyl especially C₁₋₆alkylcarbamyl such as methylcarbamyl and ethyl carbamoyl; and ##STR6##wherein R⁴ is hydrogen or alkyl having from 1 to 10 carbons; R³ is

(a) hydrogen;

(b) R² ;

(c) lower alkanoyl;

(d) cyano;

(e) haloloweralkyl;

(f) carbamyl, loweralkylcarbamyl, or diloweralkylcarbamyl;

(g) --CH₂ ONO₂ ; or

(h) --CH₂ OCOR² ;

R⁵ is hydrogen or lower alkyl; and further wherein R² and R³ may betaken together to form a ring cyclizing moiety selected from th groupconsisting of: ##STR7## e.g., to form compounds of the type: ##STR8##with the proviso that when R¹ S is the residue of a sulfur containingamino acid, then X cannot be NR⁵ ;

(ii) prodrugs having the structural formula (I) wherein ##STR9## is theresidue of any naturally occurring protein amino acid, the residue ofany N-substituted naturally occurring amino acid, which N-substituent islower alkyl or any amino acid protective group cleavable viahydrogenolysis or hydrolysis (e.g., formyl, benzyloxy, carbonyl,t-butyloxycarbonyl), or the residue of an N,N-lower-dialkyl or C₄ -C₇cycloalkylamino acid; and (iii) the non-toxic, pharmaceuticallyacceptable salts thereof.

The term "naturally occurring protein amino acid" includes withoutlimitation:

    ______________________________________                                        Glycine            Arginine                                                   Alanine            Lysine                                                     Valine             Hydroxylsine                                               Leucine            Phenylalanine                                              Isoleucine         Tyrosine                                                   Cysteine           Asparagine                                                 Cystine            Glutamine                                                  Methionine         Proline                                                    Serine             Hydroxyproline                                             Threonine          Histidine                                                  Aspartic acid      Tryptophan                                                 Glutamic acid      Pyroglutamic acid                                          ______________________________________                                    

Similarly, the import of the phrase "amino acid protective group`cleavable` via hydrogenolysis or hydrolysis" can be further gained foma review of U.S. Pat. No. 3,803,102 to Felix and U.S. Pat. No. 3,957,803to Bodor, et al.

It too will be appreciated that by "residue" of a naturally occurringamino acid there are intended not only those species wherein the "CO" ofthe R² --CO-- moiety comprising the topic prodrugs is the carbonylfunction originating from the amino acid, per se, e.g., species of type##STR10## but also such species including a free carboxyl function,e.g., species of the type ##STR11## as well as amino acid species ofamido type, wherein the --CONHR⁵ function comprises the parent aminoacid, e.g., species of the type ##STR12##

When R² comprises a heterocyclic function, representative suchheterocycles include, without limitation, and without regard to thepoint of attachment on the ring, piperazinyl, 4-methylpiperazinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyrrolyl,pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, piperidyl,morpholinyl, quinuclidinyl, isoindolinyl, indolinyl, thienyl,benzothienyl, napthothienyl, thianthrenyl, furyl, pyranyl, chromenyl,xanthenyl, phenoxathiinyl, imidazolyl, pyridyl, indolizinyl, isoindolyl,3H-indolyl, indolyl, indazolyl, purinyl, phthalazinyl, quinolyl,isoquinolyl, 4-uinolizinyl, quinoxalinyl, naphthyridinyl, cinnolinyl,pteridinyl, carbazolyl, 4aH-carbazolyl, β-carbolinyl, phenanthridinyl,acridinyl, perimidinyl, phenoxazinyl, furazanyl, isochromanyl,chromanyl, imidazolinyl, 1-methyl-azarinyl, 1-methyl-pyrrolyl,1-methyl-imidazolyl, 1-methyl-pyrazolyl, 2-methyl-isoindolyl,3H-indolyl, phtalazinyl, quinoxilinyl, quinazidinyl, phenazinyl,isothiazolyl, 10-methylphenothiazinyl, isoxazolyl, furazanyl, thevarious saturated, unsaturated or partially saturated congeners of anyof the above, and those attached to the carbonyl carbon via a loweralkylene bridge.

Even though R¹ S-- has been defined as the residue from any biologicallyactive compound, R¹ SH, the scope of this invention is not meant to belimited to these parent compounds. It should be obvious to one skilledin the arts that simple derivatives of certain functional groups whichare attached to R¹ would also fall under the definition of R¹, e.g.,acyl derivatives of hydroxyl and amino moieties, ester and amidederivatives of carboxylic acids or other standard protecting groupswhich could be easily utilized.

Likewise when an acidic or basic moiety is a part of R¹,pharmaceutically acceptable salts thereof would also be a part of thisinvention.

By "pharmaceutically acceptable salt," there are intended theconventional non-toxic salts or the quaternary ammonium salts of thecompounds of the formula (I), formed, e.g., from non-toxic inorganic ororganic acids. For example, such conventional non-toxic salts includethose derived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, fumaric, toluenesulfonic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the compounds embraced by formula (I) which contain abasic or acidic moiety by conventional chemical methods. Generally, thesalts are prepared by reacting the free base or acid with stoichiometricamounts or with an excess of the desired salt forming inorganic ororganic acid or base in a suitable solvent or various combination ofsolvents. For example, the free base can be dissolved in a mixed aqueoussolution of the appropriate acid and the salt recovered by standardtechniques, for example, by evaporation of the solution. Alternatively,the free base can be charged into an organic solvent such as a loweralkanol, a symmetrical or asymmetrical ether containing 2 to 10 carbonatoms, an alkyl ester, or mixtures thereof, and the like, and then it istreated with the appropriate acid to form the corresponding salt. Thesalt is recovered by standard recovery techniques, for example, byfiltration of the desired salt or spontaneous separation from thesolution, or it can be precipitated by the addition of a solvent inwhich the salt is insoluble and recovered therefrom.

Examples of suitable inorganic and organic solvents for performing thevarious reactions include any inorganic or organic solvent that does notadversely affect the reactants or the resulting product, includinghalogenated solvents such as methylene chloride, chloroform, carbontetrachloride, ethylene chloride, ether solvents such astetrahydrofuran, dioxane, diglyme, n-hexane, cyclooctane, benzene,heptane, cyclohexane; mixtures thereof, and like aliphatic,cylcoaliphatic and aromatic hydrocarbon solvents, water, acidifiedaqueous solutions, mixed organic and inorganic solutions, ethyl acetate,propyl acetate, and the like.

The "quaternary ammonium salts" are likewise conventional to thepharmaceutical arts, and these too are prepared via typical methodology.Moreover, either the R¹ or the R² moiety, or both, of the subjectprodrug molecules can be quaternized or otherwise comprise a saltfunction.

The compounds of the present invention are conveniently prepared via thefollowing general syntheses:

SYNTHETIC SCHEME

The prodrugs of the sulfur containing biologically active agent areprepared by stirring the appropriate mercapto compound, e.g.,methyl-N(2-methyl-3-thiopropionyl)proline with 2-4 equivalents of acompound with the formula: ##STR13## wherein X, R², and R³ are as abovedefined and Z is a suitable leaving group, e.g., chloride, bromide,iodide, dimethylamine, tosylate, etc., with or without the presence of2-4 equivalents of a base, e.g., potassim carbonate in a suitablesolvent such as acetone, methylethylketone, cyclohexanone, benzene,toluene, tetrahydrofuran, dioxane, dimethylsulfoxide or the like to forma compound having the structural formula: ##STR14##

The protective methyl group may be removed by standard methods toproduce the sulfur protected antihypertensive agent or the carboxylprotected derivative may be used as the methyl ester.

As in the case of N-(2-methyl-3-thiopropionyl)proline, the biologicallyactive mercapto containing agents may also have other reactive groups,e.g., alcohol, carboxyl, amino, which must be protected during thecourse of the reaction with ##STR15## The chemistry of protecting thesegroups is well known to one skilled in the art. The N-protected orO-protected compounds, thus, not only are useful intermediates, but arealso useful final products, also demonstrating the utility of the patentdrug species.

The reaction with ##STR16## may be run at a temperature of from -20° C.to the boiling point of the solvent. The course of the reaction isusually monitored by thin layer chromatography or nuclear magneticresonance spectroscopy or other convenient method.

The reactant ##STR17## wherein X is O, S, NR⁵, is prepared thus:##STR18##

Several representative synthetic schemes, thus, would include: ##STR19##

While all of the compounds according to the invention are characterizedby good lipid solubility and high bioavailability, are quite stable toboth air and light, and are more immune to chemical attack by thoseagents which are conventionally used in pharmaceutical preparations, thesame are nonetheless facilely chemically and/or enzymaticallymetabolized/hydrolyzed at their therapeutic sites of action, i.e., uponadministration are cleaved into the known and proven parent drugmolecule, e.g., N-acetylcysteine, per se, as well as into variousnon-toxic products of metabolism/hydrolysis, according to the followinggeneral scheme: ##STR20##

It will be appreciated that it is a critical feature of the presentinvention that the ether sulfur and the X function comprising theacyl-X-methylthioether moiety of the subject prodrug compounds beseparated by but a single carbon atom or methylene bridge. Otherwise,e.g., if the "methylene" linkage were ethylene or higher alkylene, suchcompounds would not be subject to the aforesaid chemical and/orenzymatic metabolism/hydrolysis and would not be facilely cleaved invivo, into the noted non-toxic products of metabolism/hydrolysis. Hence,such ethylene and higher alkylene congeners are inoperative and notintended herein; indeed, same could not properly be deemed or designatedas true "prodrugs."

While all of the compounds encompassed within the aforesaid genericformula (I) meet applicants' criteria, nevertheless certain compoundsremain preferred, namely, the pivalyloxymethyl, hexanoyloxymethyl,heptanoyloxymethyl, octanoyloxymethyl, n-dodecanoyloxymethyl,n-tetradecanoyloxymethyl, n-hexadecanoyloxymethyl, acetyloxymethyl,pentanoyloxymethyl, benzoyloxymethyl, benzoyloxybenzyl,propionyloxymethyl, butyryloxymethyl, benzoylaminomethyl,pivalylthiomethyl and dimethylaminoacetylaminomethyl derivatives of6-thio guanosine, 6 mercaptopurine, 6-mercapto purine riboside,thopental, N-(2-methyl-3-thio-propionyl) proline and its esters andamides and N-acetyl cysteine.

In order to further illustrate the present invention and the advantagesthereof, the following specific examples are given, it being understoodthat same are intended only as illustrative and in nowise limitative.

EXAMPLE 1 The preparation of9-β-D-Ribofuranosyl-2-amino-6-pivalyloxymethyl-thio-9H-purine2',3',5'-triacetate

To a solution of chloromethyl pivalate (106 mg) in (15 ml) sodium iodide(130 mg) was added and then stirred protected from light for 35 min. Thesupernatant was decanted from the precipitated sodium chloride and addedto a solution of thioguanosine triacetate (250 mg) in acetone (25 ml).After adding potassium carbonate (1 g), the reaction mixture was stirredfor 69 hours. The suspended solid was then filtered off and washed withacetone. The filtrate was evaporated to dryness. The residue taken inether was washed three times with water, dried over sodium sulfate andevaporated. The residue was purified by chromatography over silica gel(12.5 g). Elution with chloroform-ethyl acetate (1:1) gave the purepivalyloxy derivative 82 mg (57.4%) as a foam on vacuum drying. IR(film) 3380, 3490, 1738, 1593, 1562, 1233, 1130, 910, 755 cm⁻¹, NMR(CDCl₃) δ 1.15 (9H, s, t-Bu), 2.05 (3H, s, Ac), 2.08 (3H, s, Ac), 2.13(3H, s, Ae), 4.41 (3H, s, CH₂ OAc+4'-H), 5.20 (2H, s, NH₂), 5.80 (1H,broad, 3'-H), 5.93 (2H, s, SCH₂), 5.96 (1H, t, 2'-H), 6.0 (1H, d, 1'-H)and 7.8 (1H, s, aromatic), MS (m/e) 539 (M⁺).

EXAMPLE 2 The Preparation of9-β-D-Ribofuranosyl-6-pivalyloxymethylthio-9H-purine 2',3',5'-triacetate

Chloromethyl pivalate (112 mg) in acetone (10 ml) was stirred withsodium iodide (135 mg) in the absence of light for 40 min. The clearsolution was decanted into a solution of9-β-D-ribofuranosyl-6-thio-9H-purine 2',3',5'-triacetate (254 mg) in 30ml of acetone. Potassium carbonate (1 g) was added and stirred protectedfrom light. When the reaction was complete, the reaction mixture wasfiltered and the filtrate was evaporated. The residue was dissolved inethyl acetate and washed three times with water. The EtOAc extract wasdried over Na₂ SO₄ and evaporated to yield a residue weighing 350 mgwhich was contaminated with traces of pivalyloxymethyl halides. It wasfiltered through silica gel (12.5 g) in EtOAc. The pure compound wasobtained as a pale white waxy solid 296 mg (91.3%). IR (film) 1755,1575, 1232, 1133 cm¹⁻. NMR (CDCl₃) δ1.10 (9H, s, butyl), 2.03 (3H, s,Ac), 2.06 (3H, s, Ac), 2.15 (3H, s, Ac), 4.43 (3H, CH₂ OAc+4'-H), 5.70(1H, m, 3'-H), 6.0 (1H, k, 2'-H), 6.25 (1H, d, 1'-H), 8.2 (1H, s,aromatic) and 8.76 (1H, aromatic), MS (m/e) 524 (M⁺).

EXAMPLE 3 The Preparation of 6-(Benzamidomethylthio)purine

Chloromethylbenzamide (55.71 mg, 0.328 mmol) and 6-mercaptopurine (50mg, 0.328 mmol) were dissolved in 1.5 ml of dry DMSO-d₆ to give a clearyellow solution. The progress of the reaction was followed by monitoringchanges in the NMR spectrum. The doublet at 5.42, due tochloromethylbenzamide, had completely disappeared after 10 hours and anew doublet at 5.83 indicated the presence of the benzamidomethylthiomoiety. Chloroform was added which caused a yellow gum to precipitatewhich was washed several times with chloroform and crystallized frommethanol: mp 197°-200° C.; IR (KBR) 1720 cm⁻¹ ; NMR (pyridin-d₅)δ8.39-7.35 (m, 5, aryl), 5.99 (d, 2, --SCH₂ NH--); MS m/e 285 (M⁺).

Anal. Calcd. for C₁₃ H₁₁ N₅ SO (285.18): C, 54.74; H, 3.85; N, 24.54.Found: C, 54.46; H, 3.59; N, 24.20.

EXAMPLE 4 The Preparation of N-acetyl-S-benzamidomethyl-L-cysteine

N-acetyl-L-cysteine (0.5 g, 3.06 mmol) was dissolved in 50 ml of drydioxane. Chloromethyl benzamide (0.52 g, 3.06 mmol) was added and thecolorless solution was stirred at 25° C. for 18 hours. The dioxane wasevaporated under vacuum with minimal amount of heating to give acolorless oil: NMR (CDCl₃ +DMSO) δ8.05-7.38 (m, 5, aryl), 4.58 (d, 2,--SCH₂ NH--), 2.01 (s, 3, --CH₃).

EXAMPLE 5 The Preparation of Methyl-S-(benzamidomethyl)thioglycolate

Methyl thioglycolate (2 g, 18.84 mmol) and chloromethylbenzamide (3.2 g,18.84 mmol) was dissolved in 60 ml of dry toluene, and the clearsolution was stirred for 18 hours at 25° C. under nitrogen at which timea TLC (10% EtOAc/CH₂ Cl₂) showed that the reaction was complete. Solidmaterials were removed by filtration and the toluene was evaporated togive a pale yellow oil. Purification on silica gel (10% EtOAc/CH₂ Cl₂)yielded a colorless oil that solidified on standing: mp 65°-68° C.; IR(KBr) 3280, 1730, 1620 cm⁻¹ ; NMR (CDCl₃) δ7.98-7.25 (m, 5, aryl), 4.77(d, 2, --SCH₂ NH--), 3.77 (s, 3, --OCH₃), 3.43 (s, 2, --SCH₂ C═O).

EXAMPLE 6 The Preparation of Methyl-S-(benzamidomethyl)thioglycolatefrom N,N-Dimethylaminomethyl-benzamide

N,N-Dimethylaminomethyl-benzamide (2 g, 18.84 mmol) and methylthioglycolate (3.36 g, 18.84 mmol) were dissolved in dry toluene and thesolution was refluxed for 2 days under nitrogen. Upon cooling, somemethylenebisbenzamide crystallized out of solution and it was removed byfiltration. Evaporation of the solvent yielded an oil that crystallizedon standing: mp 65°-68° C.; IR (KBr) 3280, 1730, 1620 cm⁻¹ ; NMR (CDCl₃)δ7.98-7.25 (m, 5, aryl), 4.77 (d, 2, --SCH₂ NH--), 3.77 (s, 3, --OCH₃),3.43 (s, 2, --SCH₂ C═O).

The following compounds are also prepared utilizing those techniquesabove outlined:

                  TABLE I                                                         ______________________________________                                         ##STR21##                                                                      R.sup.1S residue                                                                             R.sup.2          R.sup.3                                                                            X                                      ______________________________________                                        NAcetyl cysteine                                                                           (CH.sub.3).sub.3 C                                                                             H      O                                        NAcetyl cysteine                                                                           (CH.sub.3).sub.3 C                                                                             CH.sub.3                                                                             S                                        Cysteine methyl ester                                                                      (CH.sub.3).sub.3 C                                                                             C.sub.2 H.sub.5                                                                      O                                        Cysteine methyl ester                                                                      C.sub.6 H.sub.5  H      NH                                       Penicillamine                                                                              CH.sub.3 (CH.sub.2).sub.5                                                                      H      O                                          Penicillamine                                                                             ##STR22##       H      O                                          Dimercaprol                                                                              C.sub.12 H.sub.25                                                                              H      S                                        Dimercaprol  (CH.sub.3).sub.3 C                                                                             CH.sub.3                                                                             O                                        N(2-methyl-3-thio-                                                                         (CH.sub.3).sub.3 C                                                                             H      O                                        propionyl)-proline                                                            N(2-methyl-3-thio-                                                                         C.sub.6 H.sub.5  CH.sub.3                                                                             NH                                       propionyl)-proline                                                            N(2-methyl-3-thio-                                                                         CH.sub.3 (CH.sub.2).sub.5                                                                      H      S                                        propionyl)-proline                                                              N(2-methyl-3-thio- propionyl)-proline                                                     ##STR23##       CF.sub.3                                                                             S                                          N(2-methyl-3-thio-                                                                       (CH.sub.3).sub.3 C                                                                             CH.sub.3                                                                             O                                        propionyl)-proline                                                            ethyl ester                                                                   N(2-methyl-3-thio-                                                                         C.sub.5 H.sub.11 CCl.sub. 3                                                                           O                                        propionyl)-proline                                                            ethyl ester                                                                   2-thio pyridine                                                                            CH.sub.2NH.sub.2 CH.sub.3                                                                             O                                        Noxide                                                                          2-thio pyridine Noxide                                                                    ##STR24##       H      O                                          6-mercapto purine                                                                        (CH.sub.3).sub.3 C                                                                             CH.sub.3                                                                             O                                          6-mercapto purine                                                                         ##STR25##       H      NH                                         6-mercapto purine                                                                        (CH.sub.3).sub.3 C                                                                             H      O                                        riboside                                                                      6-mercapto purine                                                                          CH.sub.3 (CH.sub.2).sub.3                                                                      CH.sub.3                                                                             S                                        riboside                                                                      6-thioguanosine                                                                            (CH.sub.3).sub.3 C                                                                             H      O                                        6-thioguanosine                                                                            C.sub.6 H.sub.5  CH.sub.3                                                                             NCH.sub.3                                6-thioguanosine                                                                            CH.sub.3         H      O                                        6-thioguanosine                                                                            CH.sub.3 (CH.sub.2).sub.16                                                                     H      O                                        Thiopental   (CH.sub.3).sub.3 C                                                                             H      O                                        Thiopental   CH.sub.3 (CH.sub.2).sub.5                                                                      CH.sub.3                                                                             S                                        2-Thiouracil C.sub.6 H.sub.5  C.sub.2 H.sub.5                                                                      S                                          2-Thiouracil                                                                              ##STR26##       H      O                                          Methimazole                                                                              CH.sub.3         CF.sub.3                                                                             O                                        ______________________________________                                    

EXAMPLE 7 The Preparation of S-(3-Phthalidyl)-N-acetyl-L-cysteine

To 1.63 g (0.01 mole) of N-acetyl-L-cysteine dissolved in 20 ml of hotacetonitrile was added 1.5 g (0.01 mole) of 2-phthalaldehydic acid. Thesolution was heated at reflux for 2 hr then concentrated to give ayellow gum which was triturated with THF-ether, 10:60. The insolublegummy oil was dried in vacuo to give the desired product: ¹ H NMR(CDCl₃) 10.83 (broad s, 1, CO₂ H), 8.0-7.4 (m, 4, aromatic H), 7.4-7.0(broad d, 1, --NHCOCH₃), 6.63 (d, 1, CO₂ CHOS), 5.05-4.65 (m, 1,CHONHCOCH₃), 3.6-2.8 (m, 2, CH₃ S) and 2.1 (s, 3, CH₃ S) and 2.1 (s, 3,CH₃ --CON).

EXAMPLE 8 The preparation of6-Pivalyloxymethylthio-3-pivalyloxymethylpurine and6-Pivalyloxymethylthio-9-pivalyloxymethylpurine

To 2.0 g (0.01176 mole) of 2-mercaptopurine hydrate suspended in 10 mlof CH₂ Cl₂ was added 6 ml of triethylamine. After 10 min 5.28 g (0.0351mole) of pivalyoxymethyl chloride was added to the suspension which wasthen stirred at room temperature for 2 days. The suspension wasdissolved in 100 ml of CH₂ Cl₂. The CH₂ Cl₂ solution was washed with 25ml of 2 N HCl and 25 ml of water, then it was dried over Na₂ SO₄ andconc. in vacuo to give a yellow gum. The gum was triturated with 50 mlof ether and filtered. The residue (0.48 g, mp 193°-197°, 11% yield) was6-pivalyloxymethylthio-3-pivalyloxymethylpurine: analytical sample (66mg from 100 mg in CH₂ Cl₂ -- ether, 1:5 ml) mp 198°-199°; IR (KBr) 1735cm⁻ 1 (s) (C═O); ¹ H NMR (CDCl₃) δ8.5 (s, 1, N═CH--N), 8.17 (s, 1,N═CH--N), 6.37 (s, 2, NCH₂ O₂ C), 6.01 (s, 2, S--CH₂ O₂ C) and 1.2 (s,19, (CH₃)₃ --C); TLC (silica gel, ether) R_(f) 0.0.

Anal. Calcd for C₁₇ H₂₄ N₄ O₄ S: C, 53.66; H, 6.36; N, 14.73. Found: C,53.68; H, 6.30; N, 14.80.

The ether filtrate above was chromatographed on silica gel using etheras the eluent to give 2.70 g of a colorless viscous oil which wastriturated with petroleum ether bp 30°-75° to give 1.64 g (Mp 53°-55°,36% yield) of 6-pivalyloxymethylthio-9-pivalyoxymethyl-purine as whitecrystals: IR (KBr) 1735 cm⁻¹ (s) (C═O); ¹ H NMR (CDCl₁) δ8.83 (s, 1,N═CH═N), 6.18 (s, 2, N--CH₂ O₂ C), 6.03 (s, 2, S--CH₂ O₂ C), 1.18 (s,18, (s, 18, (CH₃)₃ C); TLC (silica gel, ether) R_(f) 0.52.

Anal. Calcd for C₁₇ H₂₄ N₄ O₄ S: C, 53.66; H, 6.36; N, 14.73. Found: C,53.88; H, 6.51; N, 14.80.

When the petroleum ether filtrate above was concentrated an addition0.25 g (mp 51°-54°, 6% yield) of the 6,9-substituted product wasobtained.

EXAMPLE 9 The Preparation of 2-Pivalyloxymethylthiopyrimidine

A suspension of 1.1 g (0.01 mole) of 1-mercaptopyrimidine in 20 ml ofCH₂ Cl₂ was allowed to react with 1.05 g (0.01 mole) of triethylaminefor 5 min. Then the suspension was treated with 1.5 g (0.01 mole) ofpivalyloxymethyl chloride for 0.5 hr. Then more triethylamine (2.0 g)was added. After 0.5 hr a clear solution was obtained which almostimmediately started to form a precipitate. The suspension was stirred atroom temperature overnight. The suspension was dissolved in CH₂ Cl₂ (100ml). The CH₂ Cl₂ solution was washed with 10% HCl (25 ml) and water (25ml), then dried over Na₂ SO₄ and conc. to give a yellow oil (1.45 g).The oil was chromatographed on silica gel using ether as the eluent togive 1.1 g (49% yield) of the desired pyrimidine as a colorless oil: IR(neat) 1735 cm⁻¹ (s) (C═O); ¹ H NMR (CDCl₃) δ8.73-8.5 (m, 2, CH--N),7.2-6.93 (m, 1, C--CH═C), 5.8 (s, 2, CO₂ CH₂) and 1.17 (s, 9, (CH₃)₃--C); TLC (silica gel, ether) R_(f) 0.46. (No starting material (R_(f)0.0) could be seen).

EXAMPLE 10 The Preparation of 1-Methyl-2-pivalyloxymethylthioimidazole

To 1.53 g (0.01 mole) of pivalyloxymethyl chloride dissolved in 30 ml ofTHF was added 1.14 g (0.01 mole) of 1-methyl-2-mercaptoimidazole. Theclear yellow solution that resulted was stirred at room temperatureovernight. The solution was concentrated to give a glass which wastriturated twice with 100 ml of ether. The suspension was filtered andthe residue was dried to give 1.85 g (mp 128°-132°, 67% yield) of thedesired product as its hydrochloride. IR (KBr) 2800-2200 cm⁻¹ ; (broad,s) (N⁺ H), 1730 cm⁻¹ (s) (C═O) and 1870 and 1820 cm⁻¹ ; ¹ H NMR (CDCl₃)δ7.60 (broad s, 2, N--CH═CH--N), 5.85 (s, 2, CO₂ CH₂ S), 3.57 (s, 3,N--CH₃) and 1.18 (s, 9, (CH₃)₃ C).

Anal. Calcd for C₁₀ H₁₇ ClN₂ O₂ S: C, 45.36; H, 6.47; N, 10.58. Found:C, 45.28; H, 6.53; N, 10.60.

A portion of the hydrochloride (0.5 g) was suspended in CH₂ Cl₂ (50 ml)and neutralized with 0.2 g of NaOH dissolved in 5 ml of water byvigorously shaking the byphasic mixture until all the solid haddissolved. The CH₂ Cl₂ solution was separated dried over Na₂ SO₄ andevaporated to give the desired product as a clear, light yellow oil: IR(neat) 1730 cm⁻¹ (s) (C═O); ¹ H NMR (CDCl₃) δ7.13 (sharp m, 1,N--CH═CH--N), 6.97 (sharp m, 1, N--CH═CHN), 5.47 (s, 2, CO₂ CH₂ S), 3.67(s, 3, N--CH₃) and 1.15 (s, 9, (CH₃)₃ C); TLC (silica gel, ether) R_(f)0.26; mass spectrum (m/e), 228 (M⁺).

From the foregoing, it will be appreciated that the prodrug derivativesaccording to the inventor exhibit all of the biological and therapeuticactivity of their "parent" mercapto compounds, whether for the treatmentof hypertension, cancer, metal poisoning, excess mucus, psoriasis,hyperthyroidism or pain (general anesthesia), or any other disease stateor condition responsive to active agents, while at the same time beingcharacterized by enhanced bioavailability and physiologicalavailability, enhanced resistance to deterioration by air and light andto chemical attack, and even the ability to elicit the samepharmacological response as the parent drug form, but at lower dosages.

The dose of the prodrug administered, whether orally, topically,inhalation spray or mist, intravenous or ophthalmic solution, ointment,or the like, and whether a single dose or a daily dose, will, of course,vary with the needs of the individual. However, the dosage administeredis not subject to definite bounds, but will usually be an effectiveamount, or the equivalent on a molar basis of the pharmacologicallyactive form produced upon the metabolic release of the active drug toachieve its desired and physiological effect. See Physicians' DeskReference, 31 (1977). Moreover, for any of the broad spectrum of dosageforms into which the subject produced can be formulated see Remington'sPharmaceutical Sciences, 14th Edition (1970).

While the invention has been described in terms of various preferredembodiments, the skilled artisan will apprecitate that variousmodifications, substitutions, omissions and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims.

What is claimed is:
 1. A compound selected from the group consisting ofthose having (i) the structural formula I: ##STR27## wherein X is O, Sor NR⁵ ;R¹ S is the deprotonated residue of a biologically active agentR¹ SH which is a thiopurine derivative selected from the groupconsisting of 6-mercaptopurine and a sugar and/or an acetate derivativethereof selected from a group consisting of 6-mercaptopurineriboside and9-β-D-ribofuranosyl-6-thio-9H-purine-2',3',5'-triacetate; R² is(a)straight or branched chain alkyl having from 1 to 20 carbon atoms; (b)aryl having from 6 to 10 carbon atoms; (c) cycloalkyl having from 3 to 8carbon atoms; (d) alkenyl having from 2-6 carbon atoms; (e) cycloalkenylhaving from 5 to 8 carbon atoms; (f) carboxyalkyl or alkanoyloxyalkylhaving from 2-6 carbon atoms; R³ is(a) hydrogen; (b) R² ; (c) loweralkanoyl having from 2-6 carbon atoms; or (d) haloloweralkyl having from1-6 carbon atoms; R⁵ is hydrogen or lower alkyl having 1-6 carbon atoms;(ii) prodrugs having the structural formula (I) wherein ##STR28## is theresidue of a naturally occurring protein amino acid, the residue of aN-substituted naturally occurring amino acid, which N-substituent isC₁₋₆ alkyl or an amino acid protective group cleavable viahydrogenolysis or hydrolysis selected from the group consisting offormyl, benzyloxy, carbonyl, and t-butyloxycarbonyl, or the residue ofan N,N-lowerdialkyl or C₄ -C₇ cycloalkylamino acids; and (iii) anon-toxic, pharmaceutically acceptable salt thereof.
 2. A compound asdefined in claim 1, whereinR² is(a) straight or branched chain C₁₋₁₂alkyl; (b) phenyl; (c) C₃₋₈ cycloalkyl; (d) C₂₋₆ alkenyl; (e) C₅₋₈cycloalkenyl; (f) C₂₋₆ alkynyl; R³ is(a) hydrogen; (b) C₁₋₆ alkyl; (c)halo C₁₋₆ alkyl; (d) trichloromethyl; or (e) trifluoromethyl.
 3. Acompound of claim 2 wherein R¹ S is the residue ofa 6-mercaptopurinederivative or sugar and/or an acetate derivative thereof selected from agroup consisting of 6-mercaptopurine riboside; and9-β-ribofuranosyl-6-thio-9H-purine-2',3',5'-triacetate.
 4. The compoundof claim 3 whereinR² is(a) phenyl; or (b) straight and branched chainalkyl having from 1 to 6 carbon atoms.
 5. The compound of claim 4whereinR² is(a) phenyl; or (b) t-butyl.
 6. The compound of claim 4wherein X is NR⁵ ;R⁵ is hydrogen or methyl; and R³ is hydrogen ormethyl.
 7. The compound of claim 3 wherein R¹ S is the residue of6-mercaptopurine;R² is t-butyl; R³ is methyl and X is O.
 8. The compoundof claim 3 wherein R¹ S is the residue of 6-mercaptopurine;R² is##STR29## R³ is hydrogen; and X is NH.
 9. The compound of claim 3wherein R¹ S is the residue of 6-mercaptopurine riboside;R² is t-butyl;R³ is H; and X is O or S.
 10. The compound of claim 3 which is(a)6-(benzamidomethylthio)purine; (b)6-pivalyloxymethylthio-3-pivalyloxymethylpurine; or (c)6-pivolyloxymethylthio-9-pivalyloxymethylpurine; (d)9-β-D-ribofuranosyl-2-amino-6-pivalyloxymethylthio-9H-purine-2',3',5'-triacetate;(e)9-β-D-ribofuranosyl-6-pivolyloxymethylthio-9H-purine-2',3',5'-triacetate.11. A therapeutically effective composition of matter comprising aneffective amount of a compound as defined by claim 1, and apharmaceutically effective carrier therefor.
 12. The method of elicitingthe corresponding therapeutic response in a warm-blooded animal, whichcomprises administering to such animal an effective amount of a compoundas defined by claim 1.